Staphylococcus aureus is among the most common bacterial pathogens in human beings. The epidemiology of methicillin-resistant S. aureus (MRSA), which are strains resistant to all -lactam antibiotics, has changed dramatically in the past fifteen years. While MRSA infections before that time occurred almost exclusively within the health care environment and in patients with health care exposure, since the mid-1990s, new strains of MRSA have arisen that are causing an epidemic of infections in the community, particularly skin and soft tissue infections but also less common severe, invasive infections. These community-associated (CA-) MRSA strains differ from the older healthcare-associated (HA-) MRSA strains in the population that they infect, in the type of infections that they cause, and in the genetic characteristics of the strains themselves. MRSA is often a commensal organism, living on the skin, in the gastrointestinal tract, and in the nose of individuals, and asymptomatic carriage is thought to be common before an infection occurs. MRSA infections often recur in patients, but it is not known which patients are at highest risk for recurrence nor whether CA- or HA-strains are more likely to cause recurrence. In the era of CA-MRSA, it is not known if patients with persistent carriage of MRSA are at elevated risk of recurrent MRSA infections. There are interventions that may decrease the likelihood of recurrent MRSA infections in an individual: decolonization protocols, cleaning of fomites, antibiotic therapies, and vaccines are all potentially relevant avenues for the future control of MRSA in the community. Each of these modalities will require further study to assess its efficacy and safety. Patients with recurrent MRSA disease are likely to benefit from such interventions, and the control of MRSA infections in this population may be critical to stemming the dissemination of CA-MRSA in the U.S. In this a two-part study, using a collection of >13,800 stored clinical S. aureus strains, obtained through surveillance at the University of Chicago Medical Center (UCMC), I will attempt to define risk factors for recurrent MRSA infections. First, using existing surveillance data from UCMC in 2003-9, in a case-control study treating those with multiple infections as the cases and those with a single infection as controls, I will examine the following as risk factors for re- infection: anatomic site of first infection, genotype of first and subsequent infecting MRSA strains including CA- and HA-MRSA strain characteristics, patient demographic characteristics, previous exposures to the health care system, and patient comorbidities. Second, nesting a prospective cohort study of recurrent MRSA infections in surveillance at UCMC, I will enroll 400 patients with incident MRSA infections and monitor them for two years. I will determine how frequently these patients have recurrent MRSA infections, how commonly they seek medical attention for the infections, the presence of the risk factors for re-infection listed above, and the genotypes of MRSA strains associated with infections and any identified asymptomatic colonization to assess the role of chronic colonization in the recurrence of MRSA infections. Public Health Relevance: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA), once limited to patients with exposures to the health care system, are becoming common in the healthy population of the United States. While many people have recurrent skin, blood or other MRSA infections after treatment for a first infection, it is not known which patients are at high risk for such recurrences. The goal of this study is to determine the risk factors that predict recurrent MRSA infections by studying the demographics, medical treatments given, and medical problems of MRSA patients, the types of infection caused by MRSA, and the genetic characteristics of MRSA strains that cause initial and recurrent infections.